1. Field of the Invention
This invention relates to resorbable materials made by gelling a solution of a single polylactide enantiomer. Such materials can be used to make resorbable implantation devices of designed morphology and thickness.
2. Description of Related Art
The poly alpha-hydroxy acids are a class of synthetic aliphatic polyesters, the main polymers of which are polylactide (alternatively referred to as polylactic acid) and polyglycolide (alternatively referred to as polyglycolic acid). These materials have been investigated for use in a variety of implant systems for soft tissue and osseous repair in medicine and dentistry, since they tend to exhibit very good biocompatibility and are biodegradable in vivo. The need to remove the device after tissue repair can thereby be reduced or eliminated. The alpha-hydroxy acids are also being investigated for production of controlled release rate delivery systems for bioactive materials, such as pharmaceuticals.
The repair of osseous defects, such as developmental malformations and surgical resections, has stimulated development and application of a wide range of synthetic and natural bone repair materials or bone substitutes. Iliac crest autograft has been shown to be an effective graft material (See, for example, Goldstrohm et al., J. Trauma, 24:50-58, 1984), but the supply is limited, requiring, in some cases of segmental defect repair or tumor resorption, multiple procedures to obtain sufficient material. In addition, the removal of cancellous graft can create additional surgical trauma, increase the potential for infection, and, by lengthening the operating time, increase the risk.
These disadvantages have spurred investigations of alternative bone repair materials. Bioceramics of calcium phosphate have attracted widespread attention because of their biocompatibility and chemical similarity to the bone matrix, which results in direct bonding to bone without intervening fibrous tissue (See, Osborn et al., Biomaterials, Winter, Gibbons, Plenk (eds.), 1980). However, they tend to be brittle, difficult to shape, and remain in the repair for time periods greater than 12 months (See, Holmes et al., Clin. Orthop. Rel. Res., 188:252-62, 1984).
The ability to vary the biodegradation rate of synthetic alpha-polyesters by material selection, copolymerization, control of molecular weight, crystallinity and morphology makes them attractive for bone repair. Resorption rate can be varied from two weeks to over a year, for example, so that implant resorption may be tuned to bone repair rates (See, Hollinger et al., Clin. Orthop. Rel. Res., 207:290-305, 1986). PLA/PGA copolymers have been used alone (Hollinger, J. Biomed. Mater. Res., 17:71-82, 1983) and as binders for bioceramics (Higashi et al., Biomaterials, 7:83-87, 1986) and decalcified allogeneic bone (Schmitz et al., Clin. Orthop. Rel. Res., 237:245-55, 1988) to produce bone fillers for repairing bony deficiencies in animals.
Such polymers can also function as delivery systems for growth factor(s) as they tend to biodegrade. U.S. Pat. No. 4,578,384 discloses a protein-acidic phospholipid addition to PLA/PGA copolymer which is reported to increase bone healing rates in rat tibias relative to the copolymer. PLA could, in itself, play a dual role of bone filler and bone growth factor. Hollinger, J. Biomed. Mater. Res., 17:71-82 (1983), reported that a 50:50 copolymer of poly(L-lactide co-glycolide) increased the rate of early osseous healing when implanted in rat tibial defects. Thus, it appears that the degradation products of these linear aliphatic polyesters may play a role in the stimulation of hard and soft tissue growth, which increases the attraction of using PLA and PGA for repairing soft or hard tissue.
Metal internal fracture fixation plates, produced for example from stainless steel, frequently have an elastic modulus greater than ten times that of bone. Although plate rigidity is an advantage for achieving primary osseous union, it tends to inhibit external callus formation, which is considered a good method for restoring the strength of the broken bone to its original level (See, Kelley et al., Advances in Biomedical Polymers, Gebelein, C. G. (ed.), Plenum Press:New York, 1987). Active remodeling of the bone after fracture healing may also be compromised unless the rigid plate is removed, often resulting in stress protection and, consequently, osteoporosis and atrophy beneath the plate.
The potential advantages of internal fixation devices produced from biodegradable polymers have long been recognized. Primary bony union and callus formation could be achieved by an adequately stiff and strong plate. Load transfer to the healing bone and bone remodeling may be promoted by a gradually reducing plate stiffness as biodegradation proceeds. Finally, the need for plate removal may be eliminated by resorption of the device.
Kulkarni et al., Arch. Surg., 93:839-43 (1966), describe the production of poly(DL-lactic acid) pins for reduction of mandibular fractures in dogs. Getter et al., J Oral Surg., 30:344-48 (1972), describe the use of high molecular weight PLA plates to treat mandibular fractures in dogs. Leenslag et al., Biomaterials, 8:70-73 (1987), disclose treatment of fractured zygoma in 10 patients using high molecular weight PLA plates. Such polymers, however, tend to be absorbed very slowly. Bostman et al., J. Bone and Joint Surgery, 69-B. No. 4 (1987), describe the use of high strength, fast resorbing, self-reinforced PLA/PGA rods for routine treatment of patients with displaced malleolar fractures.
Soft tissue repair has been a major area of application for synthetic biodegradable polymers. Reul, Ann J. Surg., 134:297-99 (1977), describes the use of "Vicryl" (Polyglactin 910) sutures in general surgical and cardiothoracic procedures. Absorbable meshes are often used to perform a buttressing role for soft tissue during healing, and may also act as a scaffolding system for ingrowth of connective tissue. Greisler, Arch. Surg., 117:1425-31 (1982), describes vascular grafts produced from bi-component fabrics based on Dacron and biodegradable polyester fibers. These are reported to achieve the required low bleeding porosity at implantation and high porosity during the healing stage as degradation proceeds. Tissue regeneration is promoted by tissue growth and adherence to the biodegradable scaffold provided by the graft structure.
The lactide/glycolide polymers and copolymers tend to demonstrate an easily characterized and controllable degradation rate and tend to be nontoxic, which is advantageous for manufacture of controlled release rate delivery systems for a wide variety of bioactive materials, such as pharmaceuticals. U.S. Pat. No. 4,563,489 discloses production of a biodegradable polymer delivery system for bone morphogenetic protein based on a poly (lactide co-glycolide) copolymer. Development of suitable delivery methods is important for such therapeutic proteins since they are readily absorbed by the body. Schakenraad et al., Biomaterials, 9:116-20 (1988), describe the development of a biodegradable hollow fiber of poly(L-lactide) for controlled release of contraceptive hormone.
U.S. Pat. No. 4,719,246 discloses compositions wherein segments of poly (R-lactide) interlock or interact with segments of poly (S-lactide), producing a crystalline phase having a melting point higher than that of either component. Processes are described for preparing the above compositions, e.g., by mixing and combining the previously prepared polymeric components in a suitable solvent or in the molten state and processes for preparing gels and porous structures of the compositions. The patent discloses spontaneous gel formation from solutions of blended polylactide enantiomers on stirring. It is described that porous structures are produced from gels of the composition by a process comprising solvent exchange and evaporation.
U.S. Pat. No. 4,637,931 discloses production of a bone repair material consisting of decalcified freeze-dried bone (DFDB) and biodegradable biocompatible copolymer, namely poly[L(-) lactide co-glycolide] copolymer, which is described as being used for improving and accelerating the healing of osseous tissue.
U.S. Pat. No. 4,578,384 discloses a material, consisting of a combination of a proteolipid and a biodegradable, biocompatible copolymer which is stated to facilitate improved healing of osseous wounds when implanted at the site of the broken tissue.
The methods disclosed in Pat. Nos. 4,637,931 and 4,578,384 for producing biodegradable bone repair materials from polymer solutions generally comprise the stages of polymer dissolution, polymer precipitation in a nonsolvent, partial drying of the precipitate and compaction of wet precipitate in a mold, followed by heating/drying to produce the finished implant.
U.S. Pat. No. 4,563,489 discloses a biodegradable PLA polymer delivery system for bone morphogenetic protein (BMP) to induce formation of new bone in viable tissue. The delivery composition described is substantially pure BMP in combination with a biodegradable PLA polymer, prepared by admixing the BMP with the biodegradable polymer. The composition is implanted in viable tissue where the BMP is slowly released and induces formation of new bone.
The method for preparing the implant material of U.S. Pat. No. 4,563,489 generally comprises (1) dissolving the physiologically acceptable biodegradable polymer in a solvent such as ethanol, acetone or chloroform, (2) admixing the polymer solution with BMP to form a dispersion of BMP in the polymer solution and (3) precipitating the composite by adding a second solvent which causes precipitation of the polymer or lyophilizing the dispersion or otherwise treating the dispersion to remove it from solvent and form the BMP-PL composite. After composite formation, it is filtered, pressed or otherwise processed to remove the solvent, and the resulting composite solid is formed into the desired shape for implantation. Other additives may be included, e.g., antibiotics, prosthesis devices, radio-opacifying agents.
The delivery compositions of U.S. Pat. No. 4,563,489 have relatively small masses and are used in relatively thin layers (i.e., in the range of 1 mm to 2 mm in thickness). In one example, implants are described as being shaped by pressing the wet BMP-PL precipitate in a mold to express the second solvent prior to drying. Wet (precipitated) composite was also shaped using glass molds to produce flakes, rods, films or plates. The patent also mentions that in preferred embodiments the BMP/biodegradable polymer delivery composition is formed into a dough, rod, film, flake or otherwise shaped as desired. The patent further mentions that the BMP/PL composition, while still dispersed or dissolved in solvent, may be formed into small pellets, flakes, platelets, etc., by casting in molds and allowed to dry or harden.
Several other processing techniques have been utilized for production of resorbable implants from the synthetic alpha-polyesters, such as PLA. U.S. Pat. No. 4,776,329 discloses the production of a resorbable compressing screw for use in orthopaedic surgery by injection molding. U.S. Pat. No. 4,781,183 discloses the production of surgical structural elements, such as plates or pins, consisting of bioabsorbable or semi-bioabsorbable composites. Specifically, a bone fixation device is disclosed based on an absorbable homopolymer of L-lactide or DL-lactide or a copolymer of L-lactide and a reinforcement material. Poly (L-lactide) was selected as the preferred matrix material. The reinforcement is described to be either particulate, such as hydroxyapatite or tricalcium phosphate, or fibrous, such as alumina, polyethylene terephthalate, or ultra-high modulus polyethylene.
Composite materials used for production of bone fixation devices may be manufactured by various routes. For particulate-filled systems, filler is typically added in the desired concentration to the bulk melted polymers in a stirred reactor vessel just subsequent to polymerization. Alternatively, particulate filler, such as tricalcium phosphate, may be thoroughly mixed with the melted bioabsorbable polymer under nitrogen or vacuum.
For fiber reinforced materials, solution impregnation and lamination or melt impregnation and lamination techniques are typically utilized. In the former case, fibers or woven fabric may be immersed in a solution of the biodegradable polymer in methylene chloride. The impregnated reinforcement may be dried, then laid up in a mold to a predetermined thickness. Vacuum may be applied using a vacuum bag, then heat and compression applied to consolidate the laminate.
Melt impregnation and lamination first typically require the making of films of the biodegradable polymer by solvent casting or melt processing, or the preparation of fibrous mats by running a solution of the polymer into a non-solvent in a thin stream to form a stringy precipitate. This precipitate may be pressed into a mat at room temperature. The films or mats may then be laid between yarn or fabric layers in a mold of predetermined thickness and consolidated as above.
Poly(L-lactide)/alumina fiber laminates may be produced by laying up melt-pressed poly(L-lactide) sheets and alumina fiber fabric in a mold and consolidating under heat and pressure. Poly(L-lactide)-Kevlar laminates may be made by solution impregnation and lamination. A laminate may also be formed by impregnating 1/2 " chopped alumina fiber with poly(L-lactide) by stirring the chopped fiber in a chloroform solution of the polymer, then drying and consolidating the mixture, by hot pressing in a mold, to give a laminate containing 30% alumina by volume.
U.S. Pat. No. 4,550,449 discloses the production methods of direct machining of a high molecular weight, solid L(-) lactide polymer after removal from the reaction vessel and grinding and molding the polymer to form the desired implantable fixation device.
U.S. Pat. No. 4,645,503 discloses production of a moldable bone implant material containing approximately 65-95% hard filler particles and a binder composed of approximately 35-5% of a biocompatible, biodegradable thermoplastic polymer which has fluidic flow properties at a selected temperature at or below about 60.degree. C. Variation in biodegradation rate via the usual routes for biodegradable polymers is described, namely, (1) adjustment of molecular weight, (2) substitution of the polymer sub-unit (copolymerization), (3) blending with a slower degrading polymer, or (4) increasing the surface area for hydrolysis by varying the proportion of binder and particles to provide voids or pores in the material.
It is an object of this invention to provide improved resorbable materials and methods for making such materials which address at least some of the shortcomings of the prior art.